U.S. patent application number 11/004168 was filed with the patent office on 2005-08-18 for multiparticulate crystalline drug compositions having controlled release profiles.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Appel, Leah E., Crew, Marshall D., Friesen, Dwayne T., Herbig, Scott M., Lo, Julian B., Lyon, David K., McCray, Scott B., Ray, Roderick J., West, James B..
Application Number | 20050181062 11/004168 |
Document ID | / |
Family ID | 34652493 |
Filed Date | 2005-08-18 |
United States Patent
Application |
20050181062 |
Kind Code |
A1 |
Appel, Leah E. ; et
al. |
August 18, 2005 |
Multiparticulate crystalline drug compositions having controlled
release profiles
Abstract
A multiparticulate for controlled release of a drug comprises
crystalline drug, a glyceride having at least one alkylate
substituent of at least 16 carbon atoms, and a poloxamer, wherein
at least 70 wt % of the drug in the multiparticulate is
crystalline.
Inventors: |
Appel, Leah E.; (Bend,
OR) ; Ray, Roderick J.; (Bend, OR) ; Lyon,
David K.; (Bend, OR) ; West, James B.; (Bend,
OR) ; McCray, Scott B.; (Bend, OR) ; Crew,
Marshall D.; (Bend, OR) ; Friesen, Dwayne T.;
(Bend, OR) ; Herbig, Scott M.; (East Lyme, CT)
; Lo, Julian B.; (Old Lyme, CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
34652493 |
Appl. No.: |
11/004168 |
Filed: |
December 3, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60527329 |
Dec 4, 2003 |
|
|
|
Current U.S.
Class: |
424/489 ; 264/5;
514/255.04; 514/28; 514/355 |
Current CPC
Class: |
A61K 9/1617 20130101;
A61K 9/1641 20130101; A61K 9/1635 20130101; A61K 31/4422 20130101;
A61K 31/7032 20130101; A61K 9/1694 20130101 |
Class at
Publication: |
424/489 ;
264/005; 514/028; 514/255.04; 514/355 |
International
Class: |
B29B 009/00; A61K
031/7052; A61K 031/496; A61K 031/455 |
Claims
1. A pharmaceutical composition providing controlled release of a
drug, comprising a plurality of multiparticulates, said
multiparticulates comprising said drug wherein at least 70 wt % of
said drug is crystalline, a poloxamer and a glyceride having at
least one alkylate substituent of at least 16 carbon atoms.
2. The pharmaceutical composition of claim 1, wherein said drug is
selected from the group consisting of azithromycin, amlodipine, and
cetirizine.
3. The composition of claim 2 wherein said drug is azithromycin
dihydrate.
4. The composition of claim 1 wherein at least 80 wt % of said drug
is crystalline.
5. The composition of claim 1 wherein said alkylate substituent is
selected from the group consisting of palmitate, stearate, oleate,
linoleate, arachidate, behenate, lignocerate, ricinoleate and
mixtures thereof.
6. The composition of claim 1 wherein said glyceride is selected
from the group consisting of: mixtures of glyceryl mono-, di-, and
tribehenates; mixtures of glyceryl tripalmitate and glyceryl
tristearate; glyceryl tri-behenates; and mixtures thereof.
7. The composition of claim 1 wherein said poloxamer is selected
from the group consisting of poloxamer 188, poloxamer 237,
poloxamer 338, poloxamer 407 and mixtures thereof.
8. The composition of claim 1 wherein said poloxamer has a
molecular weight of at least 4,700 daltons.
9. The composition of claim 1 wherein said poloxamer is solid at
ambient temperatures.
10. The composition of claim 1 wherein said poloxamer is
homogeneously distributed throughout said glyceride.
11. A process for forming multiparticulates, comprising: (a)
forming a molten mixture comprising a crystalline drug, a poloxamer
and a glyceride having at least one alkylate substituent of at
least 16 carbon atoms; (b) forming droplets from said molten
mixture; and (c) solidifying said droplets to form
multiparticulates wherein at least 70 wt % of said drug in said
multiparticulates is crystalline.
12. The process of claim 11 wherein said drug is selected from the
group consisting of azithromycin, amlodipine, and cetirizine.
13. The process of claim 12 wherein said drug is azithromycin
dihydrate.
14. The process of claim 11 wherein at least 80 wt % of said drug
in said multiparticulate is crystalline.
15. The process of claim 11 wherein said molten mixture has a
viscosity of less than about 10,000 cp.
16. A method for controlling the release rate of a drug from a
multiparticulate, comprising: (a) determining a desired release
rate of said drug from said multiparticulate; (b) forming
multiparticulates comprising (1) forming a molten mixture
comprising a crystalline drug, a poloxamer and a glyceride having
at least one alkylate substituent of at least 16 carbon atoms; (2)
forming droplets from said molten mixture; and (3) solidifying said
droplets to form multiparticulates wherein at least 70 wt % of said
drug in said multiparticulates is crystalline; and (c) prior to (b)
selecting a weight ratio of said poloxamer to said glyceride to
achieve said desired release rate.
17. The method of claim 16 wherein said glyceride comprises at
least 20 wt % of said multiparticulate and said weight ratio of
said poloxamer to said glyceride is from about 0.01 to about
0.50.
18. A pharmaceutical multiparticulate comprising a drug that is at
least 70 wt % crystalline, a poloxamer and a glyceride having at
least one alkylate substituent of at least 16 carbon atoms.
19. The multiparticulate of claim 18 wherein said drug is at least
80 wt % crystalline and is selected from the group consisting of
azithromycin, amlodipine and cetirizine.
20. The multiparticulate of claim 19 wherein said drug is
azithromycin dihydrate.
21. The multiparticulate of claim 18 wherein said glyceride is
selected from the group consisting of: mixtures of glyceryl mono-,
di-, and tribehenates; mixtures of glyceryl tripalmitate and
glyceryl tristearate; glyceryl tribehenates; and mixtures
thereof.
22. The multiparticulate of claim 21 wherein said poloxamer is
selected from the group consisting of poloxamer 188, poloxamer 237,
poloxamer 338, poloxamer 407 and mixtures thereof.
Description
BACKGROUND OF THE INVENTION
[0001] Multiparticulates are well known dosage forms that comprise
a multiplicity of particles whose totality represents the intended
therapeutically useful dose of a drug. When taken orally,
multiparticulates generally disperse freely in the gastrointestinal
(GI) tract, maximize absorption, and minimize side effects. See,
for example, Multiparticulate Oral Drug Delivery (Marcel Dekker,
1994), and Pharmaceutical Pelletization Technology (Marcel Dekker,
1989).
[0002] A specific example is disclosed in Curatolo et al., U.S.
Pat. No. 6,068,859, which discloses multiparticulates that provide
controlled release of azithromycin.
[0003] Yet another example of a multiparticulate is disclosed in
Burnside, U.S. 2001/0006650 A1, published Jul. 5, 2001, which
discloses a solid solution beadlet. The beadlet comprises (i) a
hydrophobic long chain fatty acid or ester component; (ii) a
surfactant; and (iii) a therapeutic agent. The therapeutic agent
such as a drug is described as being dissolved in the hydrophobic
component to form a single phase solid solution.
[0004] Multiparticulates are often used to provide
controlled-release of a drug. One problem when formulating a
multiparticulate that controls the release of the drug is setting
the release rate of the drug. The release rate of the drug depends
on a variety of factors, including the carrier used to form the
multiparticulate and the amount of drug in the multiparticulate.
Often it is desired to provide a particular release rate. However,
it may be difficult to achieve a particular release rate using a
particular carrier composition.
[0005] Other formulation problems result from the melt-congeal
process often used to form multiparticulates. The multiparticulates
are preferably formed into round beads or spheres. However, some
carriers, when melted and then solidified, do not form round beads.
Instead, the carriers may solidify into rods, strings, or other
non-spherical shapes, often referred to as "floss." The result is
very irregularly shaped multiparticulates that are difficult to
process into dosage forms.
[0006] It is also desired to maintain the chemical and physical
stability of the drug in the multiparticulate. This is often best
achieved by maintaining the crystallinity of the drug in the
multiparticulate. Thus, it is desired to use carriers and
processing conditions that avoid solubilization of the drug and so
maintain the drug's crystallinity.
[0007] But the presence of substantial amounts of crystalline drug
in the molten carrier during the melt-congeal process presents its
own problem. The molten carrier containing the crystalline drug
must be atomized to form multiparticulates. The presence of large
amounts of crystalline drug in the molten mixture can lead to a
high viscosity of the mixture, which in turn can make it difficult
to process the molten mixture to form the multiparticulates.
[0008] Another constraint on the selection of carriers is that the
drug may react with the materials used to form the
multiparticulates. Since the melt-congeal process occurs at
elevated temperatures, the materials should be inert at elevated
temperatures as well. Thus, it is desired to use carriers that are
relatively inert to reduce degradation of the drug or other
excipients.
[0009] What is therefore desired is a multiparticulate composition
which allows controlled release of the drug over a wide range of
release rates, which allows the release rate to be set at a
predetermined rate, which may be formed using a melt-congeal
process, and which maintains the crystallinity of the drug during
the melt-congeal process and in the resulting multiparticulate.
BRIEF SUMMARY OF THE INVENTION
[0010] In a first aspect of the invention, there is provided
controlled release multiparticulates comprising crystalline drug, a
glyceride having at least one alkylate substituent of at least 16
carbon atoms, and a poloxamer, wherein at least 70 wt % of the drug
in the multiparticulate is crystalline.
[0011] In another aspect of the invention, there is provided a
method for forming multiparticulates having the above-noted
composition, comprising forming a molten mixture of the drug, the
glyceride, and the poloxamer, forming droplets from the molten
mixture and solidifying the droplets to form the
multiparticulates.
[0012] In yet another alternative aspect of the invention, a method
is provided for setting the release rate of a drug from a
multiparticulate comprising forming a multiparticulate having the
above-noted composition, but selecting a weight ratio of the
poloxamer to the glyceride so as to achieve a desired release
rate.
[0013] The multiparticulates of the present invention have several
advantages over prior art multiparticulates. First, the particular
glyceride/poloxamer mixture allows for extremely precise control of
the release rate of the drug over a wide range of release rates.
Small changes in the relative amounts of the glyceride and the
poloxamer can result in large changes in the release rate of the
drug. This allows the release rate of the drug from the
multiparticulates to be customized to a given application by
selecting the proper ratio of drug, glyceride and poloxamer. The
glyceride/poloxamer mixture provides the further advantage of
controllably releasing nearly all of the drug from the
multiparticulate.
[0014] Another advantage of the multiparticulates of the invention
is improved stability of the drug. The poloxamer component of the
multiparticulate is very inert, thus minimizing degradation of the
drug. In addition, drugs generally have a relatively low solubility
in the glyceride/poloxamer mixture. Further, the
glyceride/poloxamer mixture melts at a temperature that is
relatively low compared with the melting point of most highly
crystalline drugs. The glyceride/poloxamer mixture thus maintains
the crystallinity of the drug during the melt-congeal process and
in the resulting multiparticulate.
[0015] Yet another advantage of the present invention is that, in
some embodiments, the glyceride/poloxamer mixture allows higher
drug loading in the multiparticulate. By "drug loading" is meant
the weight fraction of drug present in the multiparticulate. The
combination of the glyceride and poloxamer provides a mixture which
when molten has low viscosity and remains flowable even when it
includes large weight fractions of crystalline drug.
[0016] The foregoing and other objectives, features, and advantages
of the invention will be more readily understood upon consideration
of the following detailed description of the invention.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0017] FIG. 1 shows a cross-sectional schematic of a
multiparticulate prior to exposure to a use environment.
[0018] FIG. 2 shows a cross-sectional schematic of the
multiparticulate of FIG. 1 after initial exposure to an aqueous
environment of use.
[0019] FIG. 3 shows a cross-sectional schematic of the
multiparticulate of FIG. 1 after prolonged exposure to an aqueous
environment of use.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0020] The multiparticulates comprise a crystalline drug, a
glyceride having at least one alkylate substituent of at least 16
carbon atoms, and a poloxamer. At least 70 wt % of the drug in the
multiparticulate is crystalline. Drugs suitable for use with the
poloxamers and glycerides and methods for making the
multiparticulates are detailed below.
[0021] The multiparticulates of the invention generally are of a
mean diameter from about 40 to about 3,000 .mu.m, with a preferred
range of 50 to 1,000 .mu.m, and most preferably from about 100 to
300 .mu.m. While the multiparticulates can have any shape and
texture, it is preferred that they be spherical, with a smooth
surface texture. These physical characteristics of the
multiparticulates improve their flow properties, permit them to be
uniformly coated (if desired), and improve their "mouth feel" and
ease of swallowing. As used herein, the term "about" means.+-.10%
of the value.
[0022] The multiparticulates of the present invention are
particularly suitable for controlled release or delayed release or
any combination of these two release profiles when introduced to a
use environment. As used herein, a "use environment" can be either
the in vivo environment of the GI tract, subdermal, intranasal,
buccal, intrathecal, ocular, intraaural, subcutaneous spaces,
vaginal tract, arterial and venous blood vessels, pulmonary tract
or intramuscular tissue of an animal, such as a mammal and
particularly a human, or the in vitro environment of a test
solution. Exemplary test solutions include aqueous solutions at
37.degree. C. comprising (1) 0.1 N HCl, simulating gastric fluid
without enzymes; (2) 0.01 N HCl, simulating gastric fluid that
avoids excessive acid degradation of azithromycin, and (3) 50 mM
KH.sub.2PO.sub.4, adjusted to pH 6.8 using KOH or 50 mM
Na.sub.3PO.sub.4, adjusted to pH 6.8 using NaOH, both of which
simulate intestinal fluid without enzymes. The inventors have also
found that for some formulations, an in vitro test solution
comprising 100 mM Na.sub.2HPO.sub.4, adjusted to pH 6.0 using NaOH
provides a discriminating means to differentiate among different
formulations on the basis of dissolution profile. It has been
determined that in vitro dissolution tests in such solutions
provide a good indicator of in vivo performance and
bioavailability. Further details of in vitro tests and test
solutions are described herein.
Drugs
[0023] The drug may be any drug that may be administered in a
crystalline form in a multiparticulate. The term "drug" as used in
this specification and the accompanying claims includes, by way of
example and not of limitation, any physiologically or
pharmacologically active substance that produces a localized or
systemic effect in animals. The term "animals" is meant to include
mammals, including human beings.
[0024] Examples of crystalline drugs employed in the devices of
this invention include, without limitation, inorganic and organic
compounds that act on the peripheral nerves, adrenergic receptors,
cholinergic receptors, nervous system, skeletal muscles,
cardiovascular smooth muscles, blood circulatory system, synaptic
sites, neuroeffector junctional sites, endocrine and hormone
systems, immunological system, reproductive system, autocoid
systems, alimentary and excretary systems, inhibitors of autocoids
and histamine systems. Preferred classes of drugs include, but are
not limited to, antihypertensives, antianxiety agents, anticlotting
agents, anticonvulsants, blood glucose-lowering agents,
decongestants, antihistamines, antitussives, antineoplastics, beta
blockers, anti-inflammatories, antipsychotic agents, cognitive
enhancers, anti-atherosclerotic agents, cholesterol-reducing
agents, antiobesity agents, autoimmune disorder agents,
anti-impotence agents, antibacterial and antifungal agents,
hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's disease
agents, antibiotics, anti-depressants, and antiviral agents,
glycogen phosphorylase inhibitors, and cholesterol ester transfer
protein inhibitors.
[0025] Each named drug should be understood to include the neutral
form of the drug and pharmaceutically acceptable forms thereof. By
"pharmaceutically acceptable forms" thereof is meant any
pharmaceutically acceptable derivative or variation, including
stereoisomers, stereoisomer mixtures, enantiomers, solvates,
hydrates, isomorphs, polymorphs, salt forms and prodrugs. Specific
examples of antihypertensives include prazosin, nifedipine,
amlodipine besylate, trimazosin and doxazosin; specific examples of
a blood glucose-lowering agent are glipizide and chlorpropamide; a
specific example of an anti-impotence agent is sildenafil and
sildenafil citrate; specific examples of antineoplastics include
chlorambucil, lomustine and echinomycin; a specific example of an
imidazole-type antineoplastic is tubulazole; a specific example of
an anti-hypercholesterolemic is atorvastatin and atorvastatin
calcium; specific examples of anxiolytics include hydroxyzine
hydrochloride and doxepin hydrochloride; specific examples of
anti-inflammatory agents include betamethasone, prednisolone,
aspirin, piroxicam, valdecoxib, carprofen, celecoxib, flurbiprofen
and (+)-N-{4-[3-(4-fluorophenoxy)pheno-
xy]-2-cyclopenten-1-yl}-N-hyroxyurea; a specific example of a
barbiturate is phenobarbital; specific examples of antivirals
include acyclovir, nelfinavir, and virazole; specific examples of
vitamins/nutritional agents include retinol and vitamin E; specific
examples of beta blockers include timolol and nadolol; a specific
example of an emetic is apomorphine; specific examples of a
diuretic include chlorthalidone and spironolactone; a specific
example of an anticoagulant is dicumarol; specific examples of
cardiotonics include digoxin and digitoxin; specific examples of
androgens include 17-methyltestosterone and testosterone; a
specific example of a mineral corticoid is desoxycorticosterone; a
specific example of a steroidal hypnotic/anesthetic is alfaxalone;
specific examples of anabolic agents include fluoxymesterone and
methanstenolone; specific examples of antidepression agents include
sulpiride,
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-eth-
ylpropyl)-amine,
3,5-dimethyl-4-(3'-pentoxy)-2-(2',4',6'-trimethylphenoxy)-
pyridine, pyroxidine, fluoxetine, paroxetine, venlafaxine and
sertraline; specific examples of antibiotics include carbenicillin
indanylsodium, bacampicillin hydrochloride, troleandomycin,
doxycyline hyclate, ampicillin, amoxicillin and penicillin G;
specific examples of anti-infectives include benzalkonium chloride
and chlorhexidine; specific examples of coronary vasodilators
include nitroglycerin and mioflazine; a specific example of a
hypnotic is etomidate; specific examples of carbonic anhydrase
inhibitors include acetazolamide and chlorzolamide; specific
examples of antifungals include econazole, terconazole,
fluconazole, voriconazole, and griseofulvin; a specific example of
an antiprotozoal is metronidazole; specific examples of
anthelmintic agents include thiabendazole and oxfendazole and
morantel; specific examples of antihistamines include astemizole,
levocabastine, cetirizine, decarboethoxyloratadine and cinnarizine;
specific examples of antipsychotics include ziprasidone,
olanzepine, thiothixene hydrochloride, fluspirilene, risperidone
and penfluridole; specific examples of gastrointestinal agents
include loperamide and cisapride; specific examples of serotonin
antagonists include ketanserin and mianserin; a specific example of
an anesthetic is lidocaine; a specific example of a hypoglycemic
agent is acetohexamide; a specific example of an anti-emetic is
dimenhydrinate; a specific example of an antibacterial is
cotrimoxazole; a specific example of a dopaminergic agent is
L-DOPA; specific examples of anti-Alzheimer's Disease agents are
THA and donepezil; a specific example of an anti-ulcer agent/H2
antagonist is famotidine; specific examples of sedative/hypnotic
agents include chlordiazepoxide and triazolam; a specific example
of a vasodilator is alprostadil; a specific example of a platelet
inhibitor is prostacyclin; specific examples of ACE
inhibitor/antihypertensive agents include enalaprilic acid,
quinapril, and lisinopril; specific examples of tetracycline
antibiotics include oxytetracycline and minocycline; specific
examples of macrolide antibiotics include erythromycin,
clarithromycin, and spiramycin; a specific example of an azalide
antibiotic is azithromycin; specific examples of glycogen
phosphorylase inhibitors include [R-(R'S')]-5-chloro-N-[2-hydroxy-3
-{methoxymethylamino}3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamide
and 5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-(2R)-hydroxy-3-((3R-
,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide; and specific
examples of cholesterol ester transfer protein inhibitors include
[2R,4S]-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifl-
uoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl
ester,
[2R,4S]-4-[3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-
-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl
ester, and [2R,4S]
4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2--
ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester.
Glycerides
[0026] A principal component of the multiparticulate is a glyceride
having at least one alkylate substituent of at least 16 carbon
atoms. Exemplary glycerides include mono-, di- and trialkyl
glycerides of palmitate, stearate, oleate, linoleate, arachidate,
behenate, lignocerate, ricinoleate, and mixtures thereof. Exemplary
commercial grades of glycerides include: COMPRITOL 888 ATO,
available from Gattefoss Corporation of Paramus, N.J., which is a
mixture of 13 to 21 wt % glyceryl monobehenate, 40 to 60 wt %
glyceryl dibehenate, and about 35 wt % glyceryl tribehenate;
DYNASAN 118, available from Huls America, Inc. of Piscataway, N.J.,
which is a glyceryl tristearate; STEROTEX NF, available from
Karishamns USA Inc. of Columbus, Ohio, which is an hydrogenated
cotton seed oil made up of about 22 wt % glyceryl tripalmitate and
less than 76 wt % glyceryl tristearate; LUBRITAB.RTM., available
from Edward Mendell Co. of Patterson, N.Y., is a hydrogenated
refined cottonseed oil made up of about 28-32 wt % glyceryl
tripalmitate and 58-62 wt % glyceryl tristearate; HYDROKOTE,
available from Karishamns USA, which is a partially hydrogenated
soybean oil made up of about 26 wt % oleate, 49 wt % linoleate, 11
wt % linolenate before hydrogenation; CASTOR WAX, available from NL
Industries, Inc., which is hydrogenated castor oil consisting
mainly of the trialkyl glyceride of hydroxystearic acid before
hydrogenation; SYNCROWAX HR-C, available from Croda, Inc. of New
York, N.Y., which is a glyceryl tribehenate; and SYNCROWAX HGL-C
also available from Croda, which is a mixture of C.sub.18 to
C.sub.36 trialkyl glycerides.
[0027] Preferred glycerides include (1) mixtures of glyceryl mono-,
di-, and tribehenate; (2) mixtures of glyceryl tripalmitate and
glyceryl tristearate; (3) glyceryl tribehenate; and mixtures of the
three.
[0028] Preferably, the glyceride has a melting point of at least
about 50.degree. C., and more preferably at least about 60.degree.
C. The melting point should be less than about 150.degree. C. to
avoid drug degradation at high processing temperatures.
Poloxamers
[0029] Another key component of the multiparticulate is a
particular class of solid polyoxyethylene-polyoxypropylene block
copolymers, also known in the pharmaceutical arts as "poloxamers."
Poloxamers are selected so as to avoid solubilization of the
crystalline drug in the multiparticulate. Such poloxamers generally
have a molecular weight ranging from about 2000 to about 15,000
daltons and have the general formula:
HO(C.sub.2H.sub.4O).sub.a(C.sub.3H.sub.6O).sub.b(C.sub.2H.sub.4O).sub.aH
[0030] wherein a is about 10 to about 150, representing blocks of
repeat units of polyoxyethylene, and b is about 20 to about 60,
representing blocks of repeat units of polyoxypropylene, depending
on the particular grade. Suitable poloxamers are sold under the
trade names PLURONIC and LUTROL available from BASF Corporation of
Mt. Olive, N.J. Preferred poloxamers have a molecular weight of at
least about 4,700 daltons and a melting point of at least about
45.degree. C. and so are solid at ambient temperatures. Being solid
at ambient temperatures has several advantages. First, the
crystalline drug has a lower solubility in solid poloxamers
relative to liquid poloxamers, and thus the drug is more likely to
remain in its crystalline form and not dissolve in the carrier.
Second, the use of a solid poloxamer provides improved physical
stability of the multiparticulate relative to the use of a liquid
poloxamer primarily because the mobility of the solid poloxamer is
lower than that of a liquid poloxamer, resulting in a reduced rate
of change in the morphology of the multiparticulate.
[0031] Preferred grades of poloxamers include poloxamer 188
(PLURONIC F68), poloxamer 237 (PLURONIC F87), poloxamer 338
(PLURONIC F108), poloxamer 407 (PLURONIC F127), the specifications
of which are given in Table A, and mixtures of those
poloxamers.
1TABLE A Average Molecular Physical Weight Poloxamer Form at
25.degree. C. a B (daltons) 188 Solid 80 27 7,680-9,510 237 Solid
64 37 6,840-8,830 338 Solid 141 44 12,700-17,400 407 Solid 101 56
9,840-14,600
[0032] Beyond their desirability from the standpoint of not
solubilizing crystalline drug, such poloxamers have several other
advantages for use in a multiparticulate. They are very inert and
so their use reduces the risk of degradation of the drug or other
excipients, even at the elevated temperatures used to form the
multiparticulates. Such poloxamers also solidify quickly and tend
not to form floss when used with the glyceride component of the
multiparticulates, thereby providing smoother, more rounded beads,
which are easier to process.
Controlled Release
[0033] The combination of the glyceride and the poloxamer in the
multiparticulate allows for the precise control of the release rate
of the drug from the multiparticulate to a use environment. The
glyceride is a hydrophobic material that, by itself, dissolves,
disperses, or erodes slowly in a use environment such as the GI
tract. The poloxamer is a hydrophilic material that acts as a
dissolution enhancer in the multiparticulate to speed the release
of the drug, yet not permit its immediate release. The addition of
a small amount of poloxamer to the glyceride can result in large
changes in the release rate of the drug.
[0034] The drug release from a multiparticulate may be modeled as a
first order process in which the dissolution rate constant, k, may
be determined by equation I:
A.sub.t=A.sub..infin..multidot.[1-e.sup.-kt] (I)
[0035] where A.sub.t is the percentage of drug released from the
multiparticulates at time t, A.sub..infin. is the percentage of
drug released from the multiparticulates over a long period of time
(such as the amount released at 180 minutes plus the amount
remaining in the multiparticulates), t is the time in minutes, and
k is the dissolution rate constant in min.sup.-1.
[0036] The present invention has the advantage that small changes
in the amount of the poloxamer present in the glyceride lead to
relatively large changes in the rate constant k. For example, for a
composition comprising 50 wt % azithromycin dihydrate and 50 wt %
of a mixture of COMPRITOL 888 ATO and LUTROL F127, changing the
poloxamer to glyceride ratio 2.1-fold (from 0.042 to 0.087 w/w)
leads to a change in the dissolution rate constant of 1.9-fold
(from 0.009 min.sup.-1 to 0.017 min.sup.-1). Similar control over
the release rates can be obtained for other drugs, with the
magnitude of the control being dependent on several factors
including (1) the nature of the drug, (2) the drug loading in the
multiparticulate, and (3) the poloxamer to glyceride ratio.
[0037] Other equations known in the art can also be used to
describe the rate of release of drugs from multiparticulates. Such
equations often require the fitting of the data so that one or more
constants that describe the drug release rate can be
determined.
[0038] The dissolution rate of drug from a multiparticulate may
also be characterized by the amount released at a specified time
following introduction of the multiparticulate to a use
environment. The specified time may be selected as convenient for
determining the release rate of drug from the multiparticulate.
Typically, times such as 30 minutes or 60 minutes are selected for
determining the amount released from the multiparticulate. To
determine the amount released, the multiparticulates are introduced
to an aqueous environment of use and the use environment is sampled
at the selected time and analyzed for the amount of drug released
by analytical methods known in the art, such as high-performance
liquid chromatograph (HPLC) analysis. The amount released may be
reported as the mass of drug released, as the fraction or
percentage of drug initially present in the multiparticulate
released, or by some other convenient measure.
[0039] The dissolution rate of drug from a multiparticulate may
also be characterized by the time required for half of the drug to
be released from the multiparticulate following introduction to a
use environment. This value, t.sub.1/2, may be determined by
measuring the amount of drug released versus time following
introduction to an aqueous environment of use using methods known
in the art.
[0040] The particular combination of glyceride and poloxamer also
results in a multiparticulate that yields substantially complete
release of the drug. Drug that remains with the multiparticulate
and not released to the use environment is termed "residual drug."
The amount of residual drug present after 30 hours in a use
environment, such as in the GI tract or in an IB solution, is often
less than 10 wt %, may be less than 5 wt %, and may even be as
little as less than 1 wt %. That is, the multiparticulate releases
at least 90 wt % of the drug, at least 95 wt % of the drug, or even
at least 99 wt % of the drug within about 30 hours after
administration to the use environment.
[0041] The amount of drug released may be determined either by in
vivo tests or by suitable in vitro tests, such as a dissolution
test in the in vitro test solutions previously described.
[0042] The combination of the glyceride and the poloxamer also
provides a mixture that has several excellent properties for
forming multiparticulates when using a melt-congeal process. The
glyceride/poloxamer mixture works well with a wide range of drugs.
The mixture is solid at ambient conditions but has a low melting
point. The melting point of a mixture of the glyceride and
poloxamer is preferably greater than about 40.degree. C., more
preferably greater than about 50.degree. C., and most preferably
greater than about 60.degree. C. Typically, the glyceride/poloxamer
mixture will have a melting point ranging from about 70.degree. C.
to 90.degree. C. This relatively low melt temperature reduces the
risk of degradation of the drug: In addition, the melt temperature
is well below the melting point of most crystalline drugs.
[0043] The combination of the glyceride and the poloxamer has a
further advantage in that the molten mixture has a relatively low
viscosity, even at high drug loading. It is preferred that the
viscosity of the molten feed be at least about 1 cp and less than
about 10,000 cp, more preferably at least 50 cp and less than about
1000 cp. As discussed above, one problem when forming
multiparticulates using the melt congeal method is that the molten
mixture must be flowable so as to be transported to an atomizer and
atomized to form beads. The crystalline drug suspended in the
molten mixture reduces the flowability of the molten mixture,
particularly as the amount of drug in the molten mixture increases.
The combination of the glyceride and poloxamer results in a molten
mixture that has low viscosity and good flowing characteristics,
even at drug loadings as high as 70 wt %.
[0044] The glyceride/poloxamer mixture can exist as separate
regions or phases of poloxamer and glyceride, as a solid solution,
that is, a single phase in which the poloxamer is homogeneously
distributed throughout the glyceride, or any combination of these
states or states that are intermediate them. In one embodiment, the
poloxamer is present in separate regions or phases that are
dispersed substantially homogeneously throughout the carrier, as
shown for example, schematically in FIG. 1. Such
glyceride/poloxamer mixtures generally have improved dissolution
properties in terms of variation in the release rate and
minimization of residual drug.
[0045] In one embodiment, the multiparticulates comprise
substantially crystalline drug particles substantially embedded in
a glyceride/poloxamer mixture, meaning that at least about 90 wt %
of the drug particles in the multiparticulate are entirely
surrounded by the glyceride/poloxamer mixture and are not exposed
to the outside surface of the multiparticulate. Preferably at least
about 95 wt %, and more preferably at least about 98 wt %, and most
preferably about 100 wt % of the drug particles are entirely
surrounded or encapsulated by the glyceride/poloxamer mixture. The
crystalline drug particles are distributed throughout the
glyceride/poloxamer mixture. The poloxamer is uniformly distributed
throughout the glyceride and is present in substantially separate
regions (that is, as a substantially separate phase). The
multiparticulates therefore comprise at least three separate and
distinct phases: (1) crystalline drug, (2) the water-insoluble
glyceride, and (3) the poloxamer, which acts as a water-soluble or
dispersible dissolution enhancer. In this embodiment, the poloxamer
is in the form of narrow channels or fibers within the
multiparticulate. These channels or fibers have a mean diameter
ranging from about 0.1 to about 30 .mu.m. The narrow channels or
fibers interconnect the drug crystals present in the
multiparticulate.
[0046] FIG. 1 shows a cross-sectional schematic of a
multiparticulate 10 prior to exposure to a use environment. The
multiparticulate comprises crystalline drug particles 12 embedded
in the glyceride/poloxamer mixture. The poloxamer 16 is
substantially homogeneously distributed throughout the glyceride
14. The poloxamer 16 is present as a separate phase from the
glyceride 14.
[0047] When such a multiparticulate is placed into an aqueous
environment of use, water dissolves or disperses the poloxamer 16,
resulting in the formation of pores or channels 26. See FIGS. 2-3,
which are schematics of the multiparticulate of FIG. 1 after
initial and prolonged exposure to an aqueous environment of use,
respectively. These pores or channels provide access of the water
in the aqueous environment of use to the embedded drug crystals,
resulting in dissolution of drug from the multiparticulate through
these pores or channels 26. As drug crystals 12 dissolve, they
provide larger cavities that provide water from the use environment
access to additional poloxamer 16, forming more pores or channels
26 and, in turn, access to more drug crystals 12 embedded in the
multiparticulate.
[0048] As shown in FIG. 3, after prolonged exposure to an aqueous
environment of use, some of the crystalline drug particles 12 have
completely dissolved, leaving behind cavities 32. The cavities 32
expose additional amounts of the poloxamer 16 and crystalline drug
particles 12 located inside the multiparticulate to the use
environment. Over time, substantially all of the crystalline drug
particles dissolve and are released to the aqueous environment of
use. By controlling the relative amount of poloxamer to glyceride,
the number of channels or pores 26 may be controlled, thus directly
affecting the release of dissolved drug from the
multiparticulate.
[0049] The relative amounts of drug, glyceride and poloxamer may be
varied to achieve the desired dose of drug and release rate. In
general, the drug may range from about 5 to about 90 wt % of the
multiparticulate, preferably about 10 to 80 wt %, more preferably
about 30 to 60 wt % of the multiparticulate. In one embodiment, the
multiparticulate has a high drug loading in which the drug is at
least 40 wt % of the multiparticulate. The amount of glyceride may
range from about 10 to about 95 wt % of the multiparticulate,
preferably about 20 to about 90 wt %, more preferably about 40 to
about 60 wt % of the multiparticulate. The amount of poloxamer may
range from about 0.1 to about 30 wt % of the multiparticulate. The
weight ratio of poloxamer to glyceride typically ranges from about
0.01 to about 0.50, depending on the desired release rate.
Generally, the higher the ratio of poloxamer to glyceride, the
faster the rate of release of drug from the multiparticulate. For
example, to obtain a t.sub.1/2 of about 30 minutes with a
multiparticulate comprising about 50 wt % drug, the poloxamer to
glyceride ratio should be about 0.1. To obtain a t.sub.1/2 of about
10 minutes with a multiparticulate comprising about 50 wt % drug,
the poloxamer to glyceride ratio should be about 0.25. Where the
poloxamer has a low melting point, the relative amounts of drug,
glyceride, poloxamer and other excipients are chosen so that the
resulting multiparticulate is solid under ambient conditions.
[0050] The multiparticulates comprise (1) crystalline drug
suspended in (2) the glyceride/poloxamer mixture. The amount of
drug that is crystalline should be at least 70 wt % of the total
amount of drug present in the multiparticulate. Since physical and
chemical stability of the drug tends to improve with increasing
amounts of crystalline drug, in some embodiments it is preferred
that the amount of drug that is crystalline is at least 80 wt %,
and more preferably at least 90 wt %. The amount of drug that is
crystalline in the multiparticulate may be determined by any
conventional technique, such as by Powder X-Ray Diffraction
(PXRD).
[0051] To maintain a high degree of drug crystallinity, the drug
preferably has a low solubility in the molten glyceride/poloxamer
mixture. This low solubility will minimize the formation of
amorphous drug during the multiparticulate formation process.
Preferably, the solubility of drug in the glyceride/poloxamer
mixture at the processing conditions is less than about 20 wt %,
more preferably less than about 10 wt %, even more preferably less
than about 5 wt %. By "solubility of drug in the
glyceride/poloxamer mixture" is meant the mass of drug dissolved in
the glyceride/poloxamer mixture divided by the total mass of
glyceride, poloxamer, and dissolved drug. The solubility of drug in
the glyceride/poloxamer mixture may be measured by slowly adding
crystalline drug to a molten sample of the glyceride/poloxamer
mixture and determining the point at which drug will no longer
dissolve in the molten sample, either visually or through
quantitative analytical techniques, such as light scattering.
Alternatively, an excess of crystalline drug may be added to a
sample of the molten glyceride/poloxamer mixture to form a
suspension. This suspension may then be filtered or centrifuged to
remove any undissolved crystalline drug and the amount of drug
dissolved in the liquid phase can be measured using standard
quantitative techniques, such as by HPLC. When performing such
tests, care should be taken to ensure the form of the drug remains
the same throughout the duration of the test. For example, if the
drug is present as a crystalline hydrate, the molten
glyceride/poloxamer mixture should contain a sufficient amount of
water such that the crystalline drug does not dehydrate while
measuring the solubility of the drug in the glyceride/poloxamer
mixture. This can be accomplished, for example, by adding water to
the molten carrier, by maintaining a high concentration of water
vapor in the atmosphere above the melt, or both. Processes to
maintain the desired crystalline form of the drug while forming
multiparticulates are disclosed more fully in commonly assigned
U.S. patent application Ser. No. ______ ("Method for Making
Pharmaceutical Multiparticulates," Attorney Docket No. PC25021),
filed concurrently herewith.
[0052] In addition to the glyceride and poloxamer the
multiparticulates may include other excipients known in the art.
One useful class of excipients includes those capable of modifying
the viscosity of the molten mixture used to form the
multiparticulates. Such viscosity-adjusting excipients may make up
from 0 to about 25 wt % of the multiparticulate, based on the total
mass of the multiparticulate. As described above, the viscosity of
the molten mixture is a key variable in obtaining multiparticulates
with a narrow particle size distribution. If the viscosity of the
molten mixture is outside of the preferred viscosity ranges given
above, a viscosity-adjusting excipient can be added to obtain a
molten mixture within the preferred viscosity range. Examples of
viscosity-reducing excipients include stearyl alcohol, cetyl
alcohol, low molecular weight polyethylene glycol (i.e., less than
about 1000 daltons), isopropyl alcohol, and water. Examples of
viscosity-increasing excipients include microcrystalline wax,
paraffin wax, synthetic wax, high molecular weight polyethylene
glycols (i.e., greater than about 20,000 daltons), ethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl
cellulose, silicon dioxide, microcrystalline cellulose, magnesium
silicate, sugars, and salts.
[0053] Other excipients may be added to adjust the release
characteristics of the multiparticulates or to improve processing
and typically make up from 0 to about 50 wt % of the
multiparticulate, based on its total mass. For example, since the
solubility of some drugs in aqueous solution decreases with
increasing pH, a base may be included in the composition to
decrease the rate at which such drugs are released in an aqueous
use environment. Examples of bases that can be included in the
composition include di- and tribasic sodium phosphate, di- and
tribasic calcium phosphate, mono-, di-, and triethanolamine, sodium
bicarbonate, sodium citrate dihydrate, and amine-functionalized
methacrylate polymers and copolymers, such as EUDRAGIT E100 from
Rohm Pharma of Darmstadt, Germany as well as other oxide,
hydroxide, phosphate, carbonate, bicarbonate and citrate salts,
including various hydrated or anhydrous forms known in the art.
Still other excipients may be added to reduce the static charge on
the multiparticulates; examples of such anti-static agents include
talc and silicon dioxide. Flavorants, colorants, and other
excipients may also be added in their usual amounts for their usual
purposes.
Preparation of Multiparticulates
[0054] The multiparticulates are made via a melt-congeal process
comprising the steps: (a) forming a molten mixture comprising the
drug, the glyceride and the poloxamer; (b) delivering the molten
mixture of step (a) to an atomizing means to form droplets from the
molten mixture; and (c) congealing the droplets from step (b) to
form multiparticulates.
[0055] The processing conditions are chosen to maintain the
crystallinity of the drug. The temperature of the molten mixture is
kept below the melting point of the drug. Preferably, at least 70
wt % of the drug remains crystalline within the molten feed, more
preferably, at least 80 wt % and most preferably at least 90 wt
%.
[0056] The term "molten mixture" as used herein refers to a mixture
of drug, glyceride, and poloxamer heated sufficiently that the
mixture becomes sufficiently fluid that the mixture may be formed
into droplets or atomized. Atomization of the molten mixture may be
carried out using any of the atomization methods described below.
Generally, the mixture is molten in the sense that it will flow
when subjected to one or more forces such as pressure, shear, and
centrifugal force, such as that exerted by a centrifugal or
spinning-disk atomizer. Thus, the drug/glyceride/poloxamer mixture
may be considered "molten" when any portion of the
drug/glyceride/poloxamer mixture becomes sufficiently fluid that
the mixture, as a whole, may be atomized. Generally, a mixture is
sufficiently fluid for atomization when the viscosity of the molten
mixture is less than about 20,000 cp, preferably less than about
15,000 cp, and most preferably less than about 10,000 cp. Often,
the mixture becomes molten when the mixture is heated above the
melting point of the glyceride/poloxamer mixture, in cases where
the glyceride/poloxamer mixture is sufficiently crystalline to have
a relatively sharp melting point; or, when the glyceride/poloxamer
mixture is amorphous, above the softening point of the
glyceride/poloxamer mixture. The molten mixture is therefore often
a suspension of solid particles in a fluid matrix. In one preferred
embodiment, the molten mixture comprises a mixture of substantially
crystalline drug particles suspended in a glyceride/poloxamer
mixture that is substantially fluid. In such cases, a portion of
the drug may be dissolved in the glyceride/poloxamer mixture and a
portion of the glyceride/poloxamer mixture may remain solid.
[0057] Virtually any process may be used to form the molten
mixture. One method involves heating the glyceride/poloxamer
mixture in a tank until it is fluid and then adding the drug to the
molten glyceride/poloxamer mixture. Generally, the
glyceride/poloxamer mixture is heated to a temperature of about
10.degree. C. or more above the temperature at which it becomes
fluid. When one or more of the glyceride/poloxamer components is
crystalline, this is generally about 10.degree. C. or more above
the melting point of the lowest melting point material of the
mixture. The process is carried out so that at least a portion of
the feed remains fluid until atomized. Once the glyceride/poloxamer
mixture has become fluid, the drug may be added to the fluid
carrier or "melt." Although the term "melt" generally refers
specifically to the transition of a crystalline material from its
crystalline to its liquid state, which occurs at its melting point,
and the term "molten" generally refers to such a crystalline
material in its fluid state, as used herein, the terms are used
more broadly, referring in the case of "melt" to the heating of any
material or mixture of materials sufficiently that it becomes fluid
in the sense that it may be pumped or atomized in a manner similar
to a crystalline material in the fluid state. Likewise "molten"
refers to any material or mixture of materials that is in such a
fluid state. Alternatively, the drug, the glyceride, and the
poloxamer may be added to the tank and the mixture heated until the
mixture has become fluid.
[0058] Once the glyceride/poloxamer mixture has become fluid and
the drug has been added, the molten mixture is mixed to ensure the
drug is uniformly distributed therein. Mixing is generally done
using mechanical means, such as overhead mixers, magnetically
driven mixers and stir bars, planetary mixers, and homogenizers.
Optionally, the contents of the tank can be pumped out of the tank
and through an in-line, static mixer or extruder and then returned
to the tank. The amount of shear used to mix the molten feed should
be sufficiently high to ensure uniform distribution of the drug in
the molten carrier. The amount of shear is kept low enough so the
form of the drug does not change, i.e., so as to cause an increase
in the amount of amorphous drug or a change in the crystalline form
of the drug. It is also preferred that the shear not be so high as
to reduce the particle size of the drug crystals. The molten
mixture can be mixed from a few minutes to several hours, the
mixing time being dependent on the viscosity of the feed and the
solubility of drug and any optional excipients in the carrier.
[0059] An alternative method of preparing the molten mixture is to
use two tanks, melting either the glyceride or the poloxamer in one
tank and the other component in another tank. The drug is added to
one of these tanks and mixed as described above. The two melts are
then pumped through an in-line static mixer or extruder to produce
a single molten mixture that is directed to the atomization process
described below.
[0060] Another method that can be used to prepare the molten
mixture is to use a continuously stirred tank system. In this
system, the drug, glyceride, and poloxamer are continuously added
to a heated tank equipped with means for continuous stirring, while
the molten feed is continuously removed from the tank. The contents
of the tank are heated such that the temperature of the contents is
about 10.degree. C. or more above the melting point of the carrier.
The drug, glyceride, and poloxamer are added in such proportions
that the molten mixture removed from the tank has the desired
composition. The drug is typically added in solid form and may be
pre-heated prior to addition to the tank. The glyceride and
poloxamer may also be preheated or even pre-melted prior to
addition to the continuously stirred tank system.
[0061] An especially preferred method of forming the molten mixture
is by an extruder. By "extruder" is meant a device or collection of
devices that creates a molten extrudate by heat and/or shear forces
and/or produces a uniformly mixed extrudate from a solid and/or
liquid (e.g., molten) feed. Such devices include, but are not
limited to single-screw extruders; twin-screw extruders, including
co-rotating, counter-rotating, intermeshing, and non-intermeshing
extruders; multiple screw extruders; ram extruders, consisting of a
heated cylinder and a piston for extruding the molten feed;
gear-pump extruders, consisting of a heated gear pump, generally
counter-rotating, that simultaneously heats and pumps the molten
feed; and conveyer extruders. Conveyer extruders comprise a
conveyer means for transporting solid and/or powdered feeds, such,
such as a screw conveyer or pneumatic conveyer, and a pump. At
least a portion of the conveyer means is heated to a sufficiently
high temperature to produce the molten mixture. The molten mixture
may optionally be directed to an accumulation tank, before being
directed to a pump, which directs the molten mixture to an
atomizer. Optionally, an in-line mixer may be used before or after
the pump to ensure the molten mixture is substantially homogeneous.
In each of these extruders the molten mixture is mixed to form a
uniformly mixed extrudate. Such mixing may be accomplished by
various mechanical and processing means, including mixing elements,
kneading elements, and shear mixing by backflow. Thus, in such
devices, the composition is fed to the extruder, which produces a
molten mixture that can be directed to the atomizer.
[0062] In one embodiment, the composition is fed to the extruder in
the form of a solid powder. The powdered feed can be prepared using
methods well known in the art for obtaining powdered mixtures with
high content uniformity. Generally, it is desirable that the
particle sizes of the drug, glyceride, and poloxamer be similar to
obtain a substantially uniform blend. However, this is not
essential to the successful practice of the invention.
[0063] An example of a process for preparing a substantially
uniform blend is as follows. First, the glyceride and poloxamer are
milled so that their particle sizes are about the same as that of
the drug; next, the drug, glyceride, and poloxamer are blended in a
V-blender for 20 minutes; the resulting blend is then de-lumped to
remove large particles; the resulting blend is finally blended for
an additional 4 minutes. In some cases it is difficult to mill the
glyceride and poloxamer to the desired particle size since many of
these materials tend to be waxy substances and the heat generated
during the milling process can gum up the milling equipment. In
such cases, small particles of the glyceride and poloxamer can be
formed using a melt- or spray-congeal process, as described below.
The resulting congealed particles of glyceride and poloxamer can
then be blended with the drug to produce the feed for the
extruder.
[0064] Another method for producing the feed to the extruder is to
melt the glyceride and poloxamer in a tank, mix in the drug as
described above for the tank system, and then cool the molten
mixture, producing a solidified mixture of drug and carrier. This
solidified mixture can then be milled to a uniform particle size
and fed to the extruder.
[0065] A two-feed extruder system can also be used to produce the
molten mixture. In this system the drug, glyceride, and poloxamer,
all in powdered form, are fed to the extruder through the same or
different feed ports. In this way, the need for blending the
components is eliminated.
[0066] Alternatively, the glyceride and poloxamer in powder form
may be fed to the extruder at one point, allowing the extruder to
melt the glyceride and poloxamer. The drug is then added to the
molten glyceride and poloxamer through a second feed delivery port
part way along the length of the extruder, thus minimizing the
contact time of the drug with the molten glyceride and poloxamer.
The closer the second feed delivery port is to the extruder exit,
the lower is the residence time of drug in the extruder.
Multiple-feed extruders can be used when optional excipients are
included in the multiparticulate.
[0067] In another method, the composition is in the form of large
solid particles or a solid mass, rather than a powder, when fed to
the extruder. For example, a solidified mixture can be prepared as
described above and then molded to fit into the cylinder of a ram
extruder and used directly without milling.
[0068] In another method, the glyceride and poloxamer can be first
melted in, for example, a tank, and fed to the extruder in molten
form. The drug, typically in powdered form, may then be introduced
to the extruder through the same or a different delivery port used
to feed the glyceride and poloxamer into the extruder. This system
has the advantage of separating the melting step for the glyceride
and poloxamer from the mixing step, minimizing contact of the drug
with the molten glyceride and poloxamer.
[0069] In each of the above methods, the extruder should be
designed such that it produces a molten mixture with the drug
crystals uniformly distributed in the glyceride/poloxamer mixture.
Generally, the temperature of the extrudate should be about
10.degree. C. or more above the temperature at which the drug and
carrier mixture becomes fluid. The various zones in the extruder
should be heated to appropriate temperatures to obtain the desired
extrudate temperature as well as the desired degree of mixing or
shear, using procedures well known in the art. As discussed above
for mechanical mixing, a minimum shear should be used to produce a
uniform molten mixture, such that the crystalline form of the drug
is unchanged and that dissolution or formation of amorphous drug is
minimized.
[0070] The feed is preferably molten prior to congealing for at
least 5 seconds, more preferably at least 10 seconds, and most
preferably at least 15 seconds, so as to ensure adequate
homogeneity of the drug/glyceride/poloxamer melt. It is also
preferred that the molten mixture remain molten for no more than
about 20 minutes to limit exposure of the drug to the molten
mixture. As described above, depending on the reactivity of the
chosen glyceride/poloxamer mixture, it may be preferable to further
reduce the time that the mixture is molten to well below 20 minutes
in order to limit drug degradation to an acceptable level. In such
cases, such mixtures may be maintained in the molten state for less
than 15 minutes, and in some cases, even less than 10 minutes. When
an extruder is used to produce the molten feed, the times above
refer to the mean time from when material is introduced to the
extruder to when the molten mixture is congealed. Such mean times
can be determined by procedures well known in the art. In one
exemplary method, a small amount of dye or other similar compound
is added to the feed while the extruder is operating under nominal
conditions. Congealed multiparticulates are then collected over
time and analyzed for the dye, from which the mean time is
determined.
[0071] When the drug is a crystalline hydrate, it may be desirable
to maintain a high water activity in the drug/glyceride/poloxamer
admixture to reduce dehydration of the drug. This can be
accomplished either by adding water to the powdered feed blend or
by injecting water directly into the extruder by metering a
controlled amount of water into a separate delivery port. In either
case, sufficient water should be added to ensure the water activity
is high enough to maintain the desired form of the crystalline
drug. Generally, it is desirable to keep the water activity of any
material in contact with drug hydrate in the 30% to 100% RH range.
This can be accomplished by ensuring that the concentration of
water in the molten carrier is 30% to 100% of the solubility of
water in the molten glyceride/poloxamer mixture at the maximum
process temperature. In some cases, a small excess of water above
the 100% water solubility limit may be added to the mixture.
[0072] Once the molten mixture has been formed, it is delivered to
an atomizer that breaks the molten feed into small droplets.
Virtually any method can be used to deliver the molten mixture to
the atomizer, including the use of pumps and various types of
pneumatic devices (e.g., pressurized vessels, piston pots). When an
extruder is used to form the molten mixture, the extruder itself
can be used to deliver the molten mixture to the atomizer.
Typically, the molten mixture is maintained at an elevated
temperature while delivering the mixture to the atomizer to prevent
solidification of the mixture and to keep the molten mixture
flowing.
[0073] Generally, atomization occurs in one of several ways,
including (1) by "pressure" or single-fluid nozzles; (2) by
two-fluid nozzles; (3) by centrifugal or spinning-disk atomizers,
(4) by ultrasonic nozzles; and (5) by mechanical vibrating nozzles.
Detailed descriptions of atomization processes can be found in
Lefebvre, Atomization and Sprays (1989) or in Perry's Chemical
Engineers' Handbook (7th Ed. 1997). Preferably, a centrifugal or
spinning-disk atomizer is used, such as the FX1 100-mm rotary
atomizer manufactured by Niro A/S (Soeborg, Denmark).
[0074] Once the molten mixture has been atomized, the droplets are
congealed, typically by contact with a gas or liquid at a
temperature below the solidification temperature of the droplets.
Typically, it is desirable that the droplets are congealed in less
than about 60 seconds, preferably in less than about 10 seconds,
more preferably in less than about 1 second. Often, congealing at
ambient temperature results in sufficiently rapid solidification of
the droplets. However, the congealing step often occurs in an
enclosed space to simplify collection of the multiparticulates. In
such cases, the temperature of the congealing media (either gas or
liquid) will increase over time as the droplets are introduced into
the enclosed space, potentially effecting the formation of the
multiparticulates or the chemical stability of the drug. Thus, a
cooling gas or liquid is often circulated through the enclosed
space to maintain a constant congealing temperature. When it is
desirable to minimize the time the drug is exposed to high
temperatures, e.g., to prevent degradation, the cooling gas or
liquid can be cooled to below ambient temperature to promote rapid
congealing, thus minimizing formation of degradants.
[0075] Additional details of melt-congeal processes are disclosed
in commonly assigned U.S. patent application Ser. No. ______
("Improved Azithromycin Multiparticulate Dosage Forms by
Melt-Congeal Processes," Attorney Docket No. PC25015) and ______
("Extrusion Process for Forming Chemically Stable Drug
Multiparticulates," Attorney Docket No. PC25122) both filed
concurrently herewith.
[0076] Following formation of the multiparticulates, it may be
desired to post-treat the multiparticulates to improve drug
crystallinity and/or the stability of the multiparticulate. In one
embodiment the multiparticulates comprise a drug, a glyceride, and
a poloxamer, the glyceride/poloxamer mixture having a melting point
of T.sub.m in .degree. C.; the multiparticulates are treated after
formation by at least one of (i) heating the multiparticulates to a
temperature of at least 35.degree. C. and less than
(T.sub.m.degree. C.-10.degree. C.), and
[0077] (ii) exposing the multiparticulates to a mobility-enhancing
agent. This post-treatment step results in an increase in drug
crystallinity in the multiparticulates and typically an improvement
in at least one of the chemical stability, physical stability, and
dissolution stability of the multiparticulates. Post-treatment
processes are disclosed more fully in commonly assigned U.S. patent
application Ser. No. ______, ("Multiparticulate Compositions with
Improved Stability," Attorney Docket No. PC11900) filed
concurrently herewith.
[0078] The multiparticulates may also be mixed or blended with one
or more pharmaceutically acceptable materials to form a suitable
dosage form. Suitable dosage forms include tablets, capsules,
sachets, oral powders for constitution, and the like.
[0079] Other features and embodiments of the invention will become
apparent from the following examples, which are given for
illustration of the invention, rather than for limiting its
intended scope.
EXAMPLE 1
[0080] Multiparticulates were made comprising 50 wt % azithromycin
dihydrate, 40 wt % of the glyceride COMPRITOL 888 ATO and 10 wt %
poloxamer 407 (of a block copolymer of ethylene and propylene
oxides commercially available as PLURONIC F127 or LUTROL F127 from
BASF, Mt. Olive, N.J.). First, 250 g crystalline azithromycin
dihydrate, 200 g of the COMPRITOL 888 ATO and 50 g of the PLURONIC
F127 were blended in a twinshell blender for 20 minutes. This blend
was then de-lumped using a Fitzpatrick L1A mill at 3000 rpm, knives
forward using a 0.0065-inch screen. The mixture was blended again
in a twinshell blender for 20 minutes, forming a preblend feed.
[0081] The preblend feed was delivered to a B&P 19-mm
twin-screw extruder (MP19-TC with a 25 L/D ratio purchased from B
& P Process Equipment and Systems, LLC, Saginaw, Mich.) at a
rate of 130 g/min, producing a molten feed suspension of the
azithromycin dihydrate in the glyceride/poloxamer carrier at a
temperature of about 90.degree. C. The feed suspension was then
delivered to the center of a spinning-disk atomizer.
[0082] The spinning disk atomizer, which was custom made, consists
of a bowel-shaped stainless steel disk of 10.1 cm (4 inches) in
diameter. The surface of the disk is heated with a thin film heater
beneath the disk to about 90.degree. C. That disk is mounted on a
motor that drives the disk of up to approximately 10,000 RPM. The
entire assembly is enclosed in a plastic bag of approximately 8
feet in diameter to allow congealing and to capture
microparticulates formed by the atomizer. Air is introduced from a
port underneath the disk to provide cooling of the
multiparticulates upon congealing and to inflate the bag to its
extended size and shape.
[0083] A suitable commercial equivalent, to this spinning disk
atomizer, is the FX1 100-mm rotary atomizer manufactured by Niro
A/S (Soeborg, Denmark).
[0084] The surface of the spinning disk atomizer was maintained at
90.degree. C., and the disk was rotated at 5500 rpm, while forming
the azithromycin multiparticulates. The mean residence time of the
azithromycin in the extruder was about 60 seconds and the total
time the azithromycin was in the molten suspension was less than
about 3 minutes. The particles formed by the spinning-disk atomizer
were congealed in ambient air and collected. The azithromycin
multiparticulates, prepared by this method, had a diameter of about
200 .mu.m.
[0085] The properties of the melt-congealed microspheres such as
particle size can be controlled by the viscosity of the melt and
processing conditions. Given the combination of the materials in
the preferred embodiments in the present invention, the viscosity
of the melt is unchanged as long as the temperature of the heating
system is kept at 90.degree. C. The size of azithromycin
multiparticulates can be controlled by the feed rate to the disk
(the amount of molten materials fed into the spinning disk
atomizer) and the disk speed. For example, particles with a
diameter of about 200 .mu.m can be formed by a combination of (1)
feed rate at 8.4 kg/hr and disk speed at 5500 RPM or (2) feed rate
at 20 kg/hr and disk speed at 5800 RPM, or (3) feed rate at 25
kg/hr and disk speed at 7100 RPM.
[0086] The so-made multiparticulates were annealed by placing
samples of them in a shallow tray at a depth of about 2 cm and the
tray was then placed in a controlled atmosphere oven at 47.degree.
C. and 70% RH for 24 hours. PXRD analysis of the multiparticulates
showed that 85 wt % of the azithromycin present was still
crystalline dihydrate, confirming the presence of two phases in the
multiparticulates.
EXAMPLES 2-6
[0087] Azithromycin-containing multiparticulates were made as in
Example 1, with the processing variables noted in Table 1. The
ratio of ingredients was varied to determine the effect on
azithromycin release. PXRD analysis confirmed that >90 wt % of
the azithromycin in the multiparticulates was crystalline
dihydrate.
2TABLE 1 Formulation (Azithromycin/ COMPRITOL 888 Feed Disk Disk
Batch Annealing Ex. ATO/PLURONIC Rate speed Temp size (.degree.
C./% RH; No. F127, wt %) (g/min) (rpm) (.degree. C.) (g) days) 1
50/40/10 130 5500 90 500 47/70; 1 2 50/45/4 140 5500 90 491 47/70;
1 3 50/46/4 140 5500 90 4968 40/75; 5 4 50/47/3 180 5500 86 1015
40/75; 5 3.45 wt % H.sub.2O added to preblend feed 5 50/48/2 130
5500 90 500 47/70; 1 6 50/50/0 130 5500 90 500 47/70; 1
[0088] The rate of release of azithromycin from the
multiparticulates of Examples 1-6 was determined using the
following procedure. A sample of the multiparticulates was placed
into a USP Type 2 dissoette flask equipped with TEFLON.RTM.-coated
paddles rotating at 50 rpm. For Examples 1-3 and 6 ,1060 mg of
multiparticulates were added to the dissolution medium; for Example
4, 1048 mg were added; for Example 5, 1000 mg were added. The flask
contained 1000 mL of 50 mM KH.sub.2PO.sub.4 buffer, pH 6.8, held at
37.0.+-.0.5.degree. C. The multiparticulates were pre-wet with 10
mL of the buffer before being added to the flask. A 3-mL sample of
the fluid in the flask was then collected at 5, 15, 30, 60, 120,
and 180 minutes following addition of the multiparticulates to the
flask. The samples were filtered using a 0.45-.mu.m syringe filter
prior to analyzing via HPLC (Hewlett Packard 1100, Waters Symmetry
C.sub.8 column, 45:30:25 acetonitrile:methanol:25 mM
KH.sub.2PO.sub.4 buffer at 1.0 mL/min, absorbance measured at 210
nm with a diode array spectrophotometer). The results of these
dissolution tests are given in Table 2.
3TABLE 2 Azithromycin Time Released Example No. (min) (%) 1 0 0 5
32 15 67 30 90 60 99 120 99 180 100 2 0 0 15 28 30 46 60 69 120 87
180 90 3 0 0 15 25 30 42 60 64 120 86 180 93 4 0 0 15 14 30 27 60
44 120 68 180 81 5 0 0 5 3 15 11 30 23 60 41 120 66 180 81 6 0 0 5
4 15 10 30 19 60 32 120 50 180 62
[0089] The dissolution rate constant k in units of min.sup.-1 for
the multiparticulates of Examples 1-6 were calculated by fitting
the data to the above-noted equation I and solving for k:
A.sub.t=A.sub..infin..multidot.1-e.sup.-kt]
[0090] where A.sub.t is the percentage of azithromycin released
from the multiparticulates at time t, A.sub..infin. is the
percentage of azithromycin released from the multiparticulates over
a long period of time (equal to the amount released at 180 minutes
plus the amount remaining in the multiparticulates after the test)
and t is the time in minutes. The so-calculated dissolution rate
constants (k) and the time required for half of the drug to be
released (t.sub.1/2) for the multiparticulates of Examples 1-6 are
given in Table 3.
4TABLE 3 Formulation (Azithromycin/ Poloxamer COMPRITOL 888 to %
Drug % Drug ATO/PLURONIC Glyceride Released Released k t.sub.1/2
Ex. No. F127, wt %) Ratio at 30 min. at 60 min. (1/min) (min) 1
50/40/10 0.25 90 99 0.077 8 2 50/45/5 0.11 46 69 0.019 33 3 50/46/4
0.09 42 64 0.017 37 4 50/47/3 0.06 27 44 0.010 63 5 50/48/2 0.04 23
41 0.009 70 6 50/50/0 0.00 19 32 0.006 105
[0091] The results in Table 3 show that as the concentration of the
poloxamer in the multiparticulates is decreased (and the ratio of
poloxamer to glyceride is decreased), the dissolution rate constant
decreases, as does the amount of drug released at 30 min and 60
min, while t.sub.1/2 increases with decreasing poloxamer to
glyceride ratio.
EXAMPLE 7
[0092] Multiparticulates were made as in Example 1 comprising
azithromycin dihydrate, the glyceride STEROTEX NF and the poloxamer
PLURONIC F127 with the processing variables noted in Table 4. PXRD
analysis of the multiparticulates confirmed that >90 wt % of the
drug present was crystalline.
5TABLE 4 Formulation (Azithromycin/ STEROTEX/ Feed Disk Disk
Annealing PLURONIC F127, Rate speed Temp Batch (.degree. C./% RH;
wt %) (g/min) (rpm) (.degree. C.) size (g) days) 50/46/4 140 5500
85 719 40/75; 5
[0093] The so-made multiparticulates were evaluated in the same
manner as those of Examples 1-6, with a sample size of 1060 mg. The
results of this dissolution test are given in Table 5.
6 TABLE 5 Azithromycin Time Released (min) (%) 0 0 15 22 30 36 60
52 120 68 180 74
[0094] From the data in Table 5, the dissolution rate constant k
was calculated as noted above and is given in Table 6. The
dissolution rate constant for Example 3 is shown again for
comparison.
7TABLE 6 Formulation (Azithromycin/ Glyceride/ % Drug % Drug
Example PLURONIC Released Released k t.sub.1/2 No. F127, wt %) at
30 min. at 60 min. (1/min) (min) 7 50/46/4 36 52 0.011 57 (with
STEROTEX) 3 50/46/4 42 64 0.017 37 (with COMPRITOL 888 ATO)
[0095] The results in Table 6 show that the dissolution rate
constant decreases for multiparticulates containing STEROTEX NF,
compared to multiparticulates containing COMPRITOL 888 ATO.
EXAMPLE 8
[0096] Multiparticulates were made comprising 50 wt % azithromycin
dihydrate, 47 wt % COMPRITOL 888 ATO, and 3 wt % LUTROL F127 using
the following procedure. First, 140 kg azithromycin dihydrate was
weighed and passed through a Quadro Comil 196S with a speed of 900
rpm, and equipped with a No. 2C-075-H050/60 screen (special round,
0.075"), a No. 2F-1607-254 impeller, and a 0.225 inch spacer
between the impeller and screen. Next, 8.4 kg of the LUTROL F127
and then 131.6 kg of the COMPRITOL 888 ATO were weighed and passed
through a Quadro 194S Comil set at 650 rpm and equipped with a No.
2C-075-R03751 screen (0.075"), a No. 2C-1601-001 impeller, and a
0.225-inch spacer between the impeller and screen. This mixture was
blended using a Gallay 38 cubic foot stainless-steel bin blender
rotating at 10 rpm for 40 minutes, for a total of 400 rotations,
forming a preblend feed.
[0097] The preblend feed was delivered to a Leistritz 50 mm
twin-screw extruder (Model ZSE 50, American Leistritz Extruder
Corporation, Somerville, N.J.) at a rate of about 20 kg/hr. The
extruder was operated in co-rotating mode at about 100 rpm, and
interfaced with a melt/spray-congeal unit. The extruder had five
segmented barrel zones and an overall extruder length of 20 screw
diameters (1.0 m). Water was injected into barrel number 2 at a
rate of 6.7 g/min (2 wt %). The extruder's rate of extrusion was
adjusted so as to produce a molten feed suspension of the
azithromycin dihydrate in the COMPRITOL 888 ATO/LUTROL F127 at a
temperature of about 90.degree. C.
[0098] The feed suspension was delivered to the spinning-disk
atomizer of Example 1, rotating at 6400 rpm. The maximum total time
the azithromycin was exposed to the molten suspension was less than
10 minutes. The particles formed by the spinning-disk atomizer were
cooled and congealed in the presence of cooling air circulated
through the product collection chamber. The mean particle size was
determined to be about 200 .mu.m using a Malvern particle size
analyzer.
[0099] The so-formed multiparticulates were post-treated by placing
a sample in a sealed barrel that was then placed in a controlled
atmosphere chamber at 40.degree. C. for 10 days. Samples of the
post-treated multiparticulates were evaluated by PXRD, which showed
that about 99% of the azithromycin in the multiparticulates was in
the crystalline dihydrate form.
[0100] To determine the dissolution rate of these
multiparticulates, a sample of the multiparticulates containing
about 2000 mgA of azithromycin was placed into a 125-mL bottle,
along with 19.36 g sucrose, 352 mg trisodium phosphate, 250 mg
magnesium hydroxide, 67 mg hydroxypropyl cellulose, 67 mg xanthan
gum, 110 mg colloidal silicon dioxide, 400 mg titanium dioxide, 140
mg cherry flavoring and 230 mg banana flavoring. Next, 60 mL of
purified water was added, and the bottle was shaken for 30 seconds.
The contents were added to a USP Type 2 dissoette flask equipped
with TEFLON.RTM.-coated paddles rotating at 50 rpm. The flask
contained 840 mL of a buffered test solution comprising 100 mM
Na.sub.2HPO.sub.4 buffer, pH 6.0, maintained at 37.0.+-.0.5.degree.
C. The bottle was rinsed twice with 20 mL of the buffer from the
flask, and the rinse was returned to the flask to make up a 900 mL
final volume. A 3 mL sample of the fluid in the flask was then
collected at 15, 30, 60, 120, and 180 minutes following addition of
the multiparticulates to the flask. The samples were filtered using
a 0.45-.mu.m syringe filter prior to analyzing via HPLC (Hewlett
Packard 1100, Waters Symmetry C.sub.8 column, 45:30:25
acetonitrile:methanol:25 mM KH.sub.2PO.sub.4 buffer at 1.0 mL/min,
absorbance measured at 210 nm with a diode array
spectrophotometer). The results of these dissolution tests are
given in Table 7.
8TABLE 7 Azithromycin Azithromycin Time Released Released Example
Test Medium (min) (mg) (%) 8 100 mM 0 0 0 Na.sub.2HPO.sub.4 15 720
36 buffer, pH 6.0, 30 1140 57 60 1620 81 120 1900 95 180 1960
98
[0101] From the data in Table 7, the dissolution rate constant k
was calculated as noted above and is given in Table 8.
9TABLE 8 Formulation (Azithromycin/ COMPRITOL 888 ATO/ % Drug %
Drug Example LUTROL F127, Released Released k t.sub.1/2 No. wt %)
at 30 min. at 60 min. (1/min) (min) 8 50/47/3* 57 81 0.029 24 *2 wt
% water added to extruder.
EXAMPLES 9-11
[0102] Multiparticulates were prepared comprising the drug
amlodipine, the glyceride COMPRITOL 888 ATO and the poloxamer
PLURONIC F127. For Example 9, the multiparticulates comprised 10 wt
% amlodipine, 60 wt % of the COMPRITOL 888 ATO and 30 wt % of the
PLURONIC F127. For Example 10, the multiparticulates comprised 10
wt % amlodipine, 70 wt % of the COMPRITOL 888 ATO and 20 wt % of
the PLURONIC F127. For Example 11, the multiparticulates comprised
10 wt % amlodipine, 80 wt % of the COMPRITOL 888 ATO and 10 wt % of
the PLURONIC F127. In each case, PXRD analysis of the
multiparticulates confirmed that >90 wt % of the drug present
was crystalline.
[0103] The multiparticulates were prepared using the following
melt-congeal procedure. First, the COMPRITOL 888 ATO and the
PLURONIC F127 were added to a sealed, jacketed stainless-steel tank
equipped with a mechanical mixing paddle. Heating fluid at
92.degree. C. was circulated through the jacket of the tank. After
about 25 minutes, the mixture had melted, having a temperature of
about 90.degree. C. This mixture was then mixed at 700 rpm for 5
minutes. Next, amlodipine that had been pre-heated to 90.degree. C.
at ambient RH was added to the melt and mixed at a speed of 700 rpm
for 5 minutes, resulting in a feed suspension of the amlodipine in
the molten components.
[0104] Using a gear pump, the feed suspension was then pumped at a
rate of 140 g/min to the center of the spinning-disk atomizer of
Example 1, the surface of which was heated to 90.degree. C. The
disk was spinning at 7000 rpm for Examples 8-9 and at 10,000 rpm
for Example 10. The particles formed by the spinning-disk atomizer
were congealed in ambient air and collected. Table 9 summarizes the
processing variables.
10TABLE 9 Formulation (Amlodipine/ COMPRITOL 888 ATO/ Stir Feed
Disk Disk Batch PLURONIC Melt time Stir rate time Rate speed Temp
size Ex. No. F127, wt %) (min) (rpm) (min) (g/min) (rpm) (.degree.
C.) (g) 9 10/60/30 25 700 5 140 7000 91 25 10 10/70/20 25 700 5 140
7000 90 25 11 10/80/10 20 700 5 140 10000 90 20
[0105] The rate of release of amlodipine from the multiparticulates
of Examples 9-11 was determined using the following procedure. A
5.5 mg sample of the multiparticulates was placed into a USP Type 2
dissoette flask equipped with TEFLON.RTM.-coated paddles rotating
at 75 rpm. The flask contained 500 mL of 0.022 M sodium acetate (pH
4.5) buffer held at 37.0.+-.0.5.degree. C. The multiparticulates
were pre-wet with 15 mL of the buffer before being added to the
flask. A 3-mL sample of the fluid in the flask was then collected
at 5, 15, 30, 45, and 60 minutes following addition of the
multiparticulates to the flask. The samples were filtered using a
0.45-.mu.m syringe filter prior to analyzing via HPLC (Hewlett
Packard 1100, Waters Norapak C.sub.18 column, 50 mM triethylamine
orthophosphate at 1.0 mL/min, absorbance measured at 237 nm with a
diode array spectrophotometer). The results of these dissolution
tests are given in Table 10.
11TABLE 10 Amlodipine Time Released Example No. (min) (%) 9 0 0 5
94 15 97 30 97 45 97 60 97 10 0 0 5 88 15 94 30 96 45 96 60 97 11 0
0 5 9 15 22 30 29 45 35 60 41
[0106] From the data in Table 10, the dissolution rate constants k
were calculated as noted above and are given in Table 11.
12TABLE 11 Formulation (Amlodipine/ % Drug % Drug Ex. COMPRITOL 888
ATO/ Released Released k t.sub.1/2 No. PLURONIC F127, wt %) at 30
min. at 60 min. (1/min) (min) 9 10/60/30 97 97 0.597 1.1 10
10/70/20 96 97 0.436 1.4 11 10/80/10 29 41 0.010 63
[0107] The results in Table 11 show that as the concentration of
the poloxamer in the multiparticulates is decreased, the
dissolution rate constant decreases.
EXAMPLES 12-14
[0108] Multiparticulates were prepared as in Examples 9-11
comprising the drug cetirizine, the glyceride COMPRITOL 888 ATO and
the poloxamer PLURONIC F127 in various ratios to determine the
effect on cetirizine release, with the processing variables noted
in Table 12. In each case, PXRD analysis of the multiparticulates
confirmed that >70 wt % of the drug present was crystalline.
13TABLE 12 Formulation (Cetirizine/ COMPRITOL 888 Stir Feed Disk
Disk Batch Ex. ATO/PLURONIC time Rate Speed Temp size No. F127, wt
%) (min) (g/min) (rpm) (.degree. C.) (g) 12 40/60/0 5 140 5500 90
20 13 40/55/5 5 140 5500 90 20 14 40/50/10 5 140 10,000 92 20
[0109] The rate of release of cetirizine from the multiparticulates
of Examples 12-14 was determined using the following procedure. A
10 mg sample of the multiparticulates was placed into 150 mL of
stirring deionized water in a flask. A 1-mL sample of the fluid in
the flask was then collected at 1, 2, 3, 4, 5, 8, 13, 15, and 25
minutes following addition of the multiparticulates to the flask.
The absorbance at 231 nm was measured using a UV-VIS
spectrophotometer. The results of these dissolution tests are given
in Table 13.
14TABLE 13 Cetirizine Time Released Example No. (min) (%) 12 0 0 1
10 2 19 3 27 4 35 5 41 8 57 12 72 14 77 25 92 13 0 0 1 11 2 22 3 31
4 38 5 45 8 62 12 76 14 80 26 93 14 0 0 1 61 2 84 3 94 4 97 5 99 8
100 13 100 15 100
[0110] From the data in Table 13, the dissolution rate constants
were calculated as noted above and are given in Table 14.
15 TABLE 14 Formulation (Cetirizine/ COMPRITOL 888 Ex. ATO/PLURONIC
k t.sub.1/2 No. F127, wt %) (1/min) (min) 12 40/60/0 0.597 5.9 13
40/55/5 0.436 5.2 14 40/50/10 0.010 0.66
[0111] The results in Table 14 show that as the concentration of
the poloxamer in the multiparticulates is increased, the
dissolution rate constants increase.
[0112] The terms and descriptions which have been employed in the
foregoing specification are used therein as terms of description
and not of limitation, and there is no intention, in the use of
such terms and expressions, of excluding equivalents of the
features shown and described or portions thereof, it being
recognized that the scope of the invention is defined and limited
by the claims which follow.
* * * * *